Optimal beneficial effects of many modern vaccines require the use of vaccine adjuvants that enhance the immune response while maintaining systemic safety and minimal side reactions after injection. Lipopolysaccharides (LPS) are the major surface molecule of, and occur exclusively in, the external leaflet of the outer membrane of gram-negative bacteria. LPS impede destruction of bacteria by serum complement and phagocytic cells, and are involved in adherence for colonization. LPS are a group of structurally related complex molecules of approximately 10,000 Daltons that contain lipid A, which is the innermost region of LPS that serves as the hydrophobic anchor and comprises phosphorylated glucosamine disaccharide units carrying long chain fatty acids.
The biological activities of LPS, such as lethal toxicity, pyrogenicity, and adjuvanticity, have been shown to be related to the lipid A moiety. Both LPS and lipid A have long been known for their strong adjuvant effects, but the high toxicity of these molecules has limited their use in vaccine formulations. Significant scientific effort has occurred towards reducing the toxicity of LPS or lipid A while maintaining their adjuvanticity.
Other commonly used non-human adjuvants are Quillaja saponins, which are a mixture of amphipathic triterpene glycosides extracted from the bark of the tree Quillaja saponaria. Crude saponins have been employed as veterinary adjuvants. Quil-A is a partially purified aqueous extract of the Quillaja saponin material, and QS-21 is an HPLC purified fraction of Quil A. Methods of producing QS-21 (referred to as QA21) are disclosed in U.S. Pat. No. 5,057,540. One of the major side effects of using saponins such as QS-21, however, is its cytotoxicity. Specifically, although the exact cytotoxic mechanism is currently unknown, saponins cause hemolysis, which is the rupturing or lysis of red blood cells.
What is needed is a vaccine delivery composition that includes adjuvants for bolstering the immune response, but without the associated cytotoxicity.